H4C14

Summary

H4C14 (H4 clustered histone 14, HGNC:4794) is a protein-coding gene on chromosome 1q21.2, encoding Histone H4 (P62805). Core component of nucleosome.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in a histone cluster on chromosome 1. This gene is one of four histone genes in the cluster that are duplicated; this record represents the centromeric copy.

Source: NCBI Gene 8370 — RefSeq curated summary.

At a glance

• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4794
Approved symbol	H4C14
Name	H4 clustered histone 14
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000270882
Ensembl biotype	protein_coding
OMIM	142750
Entrez	8370

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 nonsense_mediated_decay, 1 protein_coding

ENST00000578186, ENST00000613412, ENST00000614272, ENST00000618193

RefSeq mRNA: 1 — MANE Select: NM_003548 NM_003548

CCDS: CCDS30847

Canonical transcript exons

ENST00000578186 — 1 exons

Exon	Start	End
ENSE00003541054	149832657	149833052

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 99.06.

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	99.06	gold quality
adrenal tissue	UBERON:0018303	92.72	gold quality
monocyte	CL:0000576	89.58	gold quality
colonic epithelium	UBERON:0000397	89.56	gold quality
bone marrow	UBERON:0002371	88.28	gold quality
leukocyte	CL:0000738	88.10	gold quality
blood	UBERON:0000178	84.59	gold quality
corpus callosum	UBERON:0002336	84.57	gold quality
tonsil	UBERON:0002372	83.12	gold quality
urinary bladder	UBERON:0001255	81.22	gold quality
right adrenal gland cortex	UBERON:0035827	80.01	gold quality
lymph node	UBERON:0000029	80.00	gold quality
right adrenal gland	UBERON:0001233	79.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.35	gold quality
prostate gland	UBERON:0002367	78.95	gold quality
cortical plate	UBERON:0005343	78.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.96	gold quality
gall bladder	UBERON:0002110	77.53	gold quality
ventricular zone	UBERON:0003053	76.92	gold quality
uterine cervix	UBERON:0000002	76.28	gold quality
granulocyte	CL:0000094	76.27	gold quality
ganglionic eminence	UBERON:0004023	76.13	gold quality
kidney	UBERON:0002113	75.45	gold quality
adult mammalian kidney	UBERON:0000082	75.40	gold quality
adrenal gland	UBERON:0002369	75.05	gold quality
popliteal artery	UBERON:0002250	74.87	gold quality
apex of heart	UBERON:0002098	74.83	gold quality
tibial artery	UBERON:0007610	74.78	gold quality
mucosa of stomach	UBERON:0001199	74.73	gold quality
duodenum	UBERON:0002114	74.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, CUX1, E2F4, IRF2, MYC, SP1

Literature-anchored findings (GeneRIF, showing 7)

• assessed the functional coupling between chromatin organization and regulation of histone H4/n gene expression during HL-60 differentiation into the monocyte/macrophage lineage (PMID:12556504)
• deiminated residues were present in H2A (1-56) and H4 (1-52) (PMID:15823041)
• Loss of the H4 arginine 3 methylation mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. (PMID:19234465)
• H2B and H4 histones were mobilized during herpes simplex virus 1 infection and became available to bind to viral genomes. (PMID:21994445)
• NASP balances the activity of the heat shock proteins Hsc70 and Hsp90 to direct H3-H4 for degradation by chaperone-mediated autophagy (PMID:22195965)
• PRMT1 regulates the tumor-initiating properties of esophageal squamous cell carcinoma through histone H4 arginine methylation coupled with transcriptional activation. (PMID:31043582)
• Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. (PMID:35303422)

Cross-species orthologs

0 orthologs

Paralogs (14): H4C8 (ENSG00000158406), H4C3 (ENSG00000197061), H4C11 (ENSG00000197238), H4C16 (ENSG00000197837), H4C15 (ENSG00000270276), H4C12 (ENSG00000273542), H4C6 (ENSG00000274618), H4C13 (ENSG00000275126), H4C7 (ENSG00000275663), H4C9 (ENSG00000276180), H4C5 (ENSG00000276966), H4C4 (ENSG00000277157), H4C1 (ENSG00000278637), H4C2 (ENSG00000278705)

Protein

Protein identifiers

Histone H4 — P62805 (reviewed: P62805)

All UniProt accessions (2): P62805, B2R4R0

UniProt curated annotations — full annotation on UniProt →

Function. Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.

Subunit / interactions. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers. Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct. Interacts with NASP; NASP is a histone chaperone that stabilizes and maintains a soluble pool of Histone H3-H4 dimers.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin. Acetylated as part of spermatogenesis progression prior to histone-to-protamine exchange. Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation. Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage. Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3). Monomethylation is performed by KMT5A/SET8. Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing. Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators. H4K20me2 and H4K20me3 are demethylated into monomethyl (H4K20me1) by RSBN1. H4K20me1, H4K20me2 and H4K20me3 are demethylated by RAD23A and RAD23B. H4K20me1 is demethylated by PHF8. Acetyl-methylated at Lys-6 and Lys-13 (H4K5acme and H4K12acme, respectively), acetyl-methylation is an epigenetic mark of active chromatin associated with increased transcriptional initiation. Acetyl-methylation is formed by acetylation by EP300/p300 of lysine residues that are already monomethylated on the same side chain. H4K5acme and H4K12acme marks specifically bind BRD2. Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me). Ubiquitinated; by PHF7. Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage. Sumoylated, which is associated with transcriptional repression. Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes. Butyrylation of histones marks active promoters and competes with histone acetylation. Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription. Delactylated by SIRT3 at Lys-17 (H4K16la).

Disease relevance. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 1 (TEBIVANED1) [MIM:619758] An autosomal dominant disorder with onset in infancy, characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED1 is caused by variants in H4C3. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 2 (TEBIVANED2) [MIM:619759] An autosomal dominant disorder characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, absent speech, and characteristic dysmorphic facial features, including hypertelorism, abnormal nose, and wide mouth. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED2 is caused by variants in H4C11. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 3 (TEBIVANED3) [MIM:619950] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED3 is caused by variants in H4C5. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 4 (TEBIVANED4) [MIM:619951] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED4 is caused by variants in H4C9. Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.

Similarity. Belongs to the histone H4 family.

RefSeq proteins (1): NP_003539* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001951	Histone_H4	Family
IPR004823	TAF_TATA-bd_Histone-like_dom	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR019809	Histone_H4_CS	Conserved_site
IPR035425	CENP-T/H4_C	Domain

Pfam: PF15511

UniProt features (138 total): modified residue 94, sequence variant 17, cross-link 8, strand 4, helix 4, mutagenesis site 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

626 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3F9X	X-RAY DIFFRACTION	1.25
8PEF	X-RAY DIFFRACTION	1.28
5TEG	X-RAY DIFFRACTION	1.3
3UVW	X-RAY DIFFRACTION	1.37
8UK5	X-RAY DIFFRACTION	1.4
1ZKK	X-RAY DIFFRACTION	1.45
4YY6	X-RAY DIFFRACTION	1.45
3F9Y	X-RAY DIFFRACTION	1.5
3QZT	X-RAY DIFFRACTION	1.5
4YYI	X-RAY DIFFRACTION	1.5
4YYM	X-RAY DIFFRACTION	1.5
5FFW	X-RAY DIFFRACTION	1.5
2BQZ	X-RAY DIFFRACTION	1.5
4YYD	X-RAY DIFFRACTION	1.52
8B5C	X-RAY DIFFRACTION	1.58
6RXS	X-RAY DIFFRACTION	1.6
3F9W	X-RAY DIFFRACTION	1.6
3F9Z	X-RAY DIFFRACTION	1.6
6VO5	X-RAY DIFFRACTION	1.6
7M98	X-RAY DIFFRACTION	1.6
2IG0	X-RAY DIFFRACTION	1.7
3O36	X-RAY DIFFRACTION	1.7
4QUT	X-RAY DIFFRACTION	1.7
5YE3	X-RAY DIFFRACTION	1.7
4YYH	X-RAY DIFFRACTION	1.74
8TGP	X-RAY DIFFRACTION	1.76
4YYK	X-RAY DIFFRACTION	1.79
5YE4	X-RAY DIFFRACTION	1.8
3QZS	X-RAY DIFFRACTION	1.8
4QUU	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62805-F1	90.90	0.75

Antibody-complex structures (SAbDab): 21 — 5YE3, 5YE4, 6E0C, 6E0P, 7K5X, 7K5Y, 7K60, 7K61, 7K63, 7U0G, 7U0I, 7U0J, 8DK5, 8EVG, 8EVH, 8EVI, 8EVJ, 8SPS, 8SPU, 8SYP, 8VFX

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (102): 4, 21, 32, 32, 60, 80, 92, 92, 6, 6, 6, 6, 6, 6, 6, 6, 9, 9, 9, 9 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
13	impaired methylation by n6amt1.
32	abolished ufmylation.

Function

Pathways and Gene Ontology

Reactome pathways

60 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3214842	HDMs demethylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-427359	SIRT1 negatively regulates rRNA expression
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-5334118	DNA methylation
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 201 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOZGIT_ESR1_TARGETS_DN, GOBP_TELOMERE_ORGANIZATION, MODULE_503, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_REGULATION_OF_HEMOPOIESIS, MODULE_195, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION

GO Biological Process (5): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), telomere organization (GO:0032200), negative regulation of megakaryocyte differentiation (GO:0045653), protein localization to CENP-A containing chromatin (GO:0061644)

GO Molecular Function (5): DNA binding (GO:0003677), RNA binding (GO:0003723), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), protein-containing complex (GO:0032991), CENP-A containing nucleosome (GO:0043505), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Chromatin modifying enzymes	5
Cellular Senescence	3
Depyrimidination	2
Depurination	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Epigenetic regulation of gene expression	1
Mitotic Prophase	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nucleic acid binding	2
chromatin	2
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
megakaryocyte differentiation	1
negative regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
structural molecule activity	1
protein dimerization activity	1
binding	1
chromosomal region	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
nucleosome	1
CENP-A containing chromatin	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

672 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0915”(physical association)	0.950
H4C16	ASF1A	psi-mi:“MI:0915”(physical association)	0.950
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
H3C1	H4C16	psi-mi:“MI:0915”(physical association)	0.890
H4C16	H3C1	psi-mi:“MI:0407”(direct interaction)	0.890
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
TP53BP1	H4C16	psi-mi:“MI:0407”(direct interaction)	0.870
H3-3A	H4C16	psi-mi:“MI:0915”(physical association)	0.860
H3-3A	H4C16	psi-mi:“MI:0914”(association)	0.860
H3-3A	H4C16	psi-mi:“MI:0407”(direct interaction)	0.860
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (3544): RBBP4 (Affinity Capture-Western), HIST1H4A (Affinity Capture-Western), HIST4H4 (Biochemical Activity), HIST4H4 (Affinity Capture-MS), HIST2H4B (Affinity Capture-MS), HIST4H4 (Two-hybrid), ASF1A (Two-hybrid), HIST4H4 (Biochemical Activity), HIST4H4 (Biochemical Activity), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4A (Biochemical Activity)

ESM2 similar proteins: P02309, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62785, P62786, P62787, P62788, P62794, P62797, P62798, P62799, P62800, P62801, P62802, P62803, P62805, P62806, P62887, Q27443, Q27765, Q43083, Q4R362, Q5RCS7, Q6LAF1, Q6LAF3, Q6PMI5, Q6V9I2, Q6WV72, Q6WV73, Q6WV90, Q6WZ83, Q71V09

Diamond homologs: P02309, P04914, P04915, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62776, P62777, P62778, P62779, P62780, P62781, P62782, P62783, P62784, P62785, P62786, P62787, P62788, P62790, P62791, P62792, P62793, P62794, P62795, P62796, P62797, P62798, P62799, P62800, P62801, P62802, P62803

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
TP53BP1	unknown	H4C1	binding
MAML1	“down-regulates activity”	H4C1	acetylation
“Integrator complex”	“down-regulates quantity by repression”	H4C1	“transcriptional regulation”
KAT5	“down-regulates activity”	H4C1	acetylation
H4C1	“up-regulates activity”	BRD2	relocalization
H4C1	“up-regulates activity”	BRD4	relocalization
H4C1	“up-regulates activity”	BRDT	relocalization
H4C1	“form complex”	“Nucleosome_H3.3 variant”	binding
“MSL acetyltransferase”	“down-regulates activity”	H4C1	acetylation
UFL1	“up-regulates activity”	H4C1	ubiquitination
SLBP	“up-regulates quantity by expression”	H4C1	“translation regulation”
“NSL histone acetyltransferase”	“down-regulates activity”	H4C1	acetylation
“NuA4 complex”	“down-regulates activity”	H4C1	acetylation
DTX3L	“down-regulates activity”	H4C1	monoubiquitination
“BRCA1-BARD1 complex”	“up-regulates activity”	H4C1	ubiquitination
H4C1	“form complex”	“CENP-A nucleosome”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.2 variant”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1t variant”	binding
HAT1	“down-regulates activity”	H4C1	acetylation
H4C1	“form complex”	Nucleosome	binding
KMT5C	“down-regulates activity”	H4C1	methylation
KMT5B	“down-regulates activity”	H4C1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	5	40.5×	1e-06
Notch-HLH transcription pathway	6	29.5×	6e-07
NOTCH1 Intracellular Domain Regulates Transcription	8	22.9×	3e-08
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	12	22.0×	3e-11
Packaging Of Telomere Ends	8	21.2×	7e-08
FXIIa activates plasma kallikrein-kinin system	10	20.9×	2e-09
Condensation of Prophase Chromosomes	11	20.7×	3e-10
NuRD complex assembly	12	20.4×	7e-11

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression, epigenetic	6	25.3×	2e-05
nucleosome assembly	16	23.6×	5e-15
heterochromatin formation	8	21.5×	1e-06
epigenetic regulation of gene expression	5	20.2×	3e-04
chromatin organization	12	12.5×	9e-08
antimicrobial humoral immune response mediated by antimicrobial peptide	5	8.5×	1e-02
chromatin remodeling	11	8.4×	1e-05
DNA damage response	10	5.6×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

171 predictions. Top by Δscore:

Variant	Effect	Δscore
1:149832940:G:GT	donor_gain	0.7300
1:149832889:G:GT	donor_gain	0.7100
1:149832727:GGCGC:G	donor_gain	0.7000
1:149832883:A:AG	donor_gain	0.6900
1:149832840:CG:C	acceptor_gain	0.6700
1:149832884:T:G	donor_gain	0.6600
1:149832713:GCT:G	donor_gain	0.6500
1:149832699:A:T	donor_gain	0.6400
1:149832840:CGAGG:C	acceptor_gain	0.6300
1:149832889:G:T	donor_gain	0.6200
1:149832748:GTCT:G	donor_gain	0.6100
1:149832749:TCTT:T	donor_gain	0.6100
1:149832840:C:CA	acceptor_gain	0.6100
1:149832840:C:G	acceptor_gain	0.6100
1:149832812:GCGT:G	donor_gain	0.6000
1:149832943:GTGGT:G	donor_gain	0.6000
1:149832945:G:GA	donor_gain	0.6000
1:149832841:G:GC	acceptor_gain	0.5900
1:149832940:G:T	donor_gain	0.5900
1:149832839:ACGAG:A	acceptor_gain	0.5700
1:149832838:TACG:T	acceptor_gain	0.5600
1:149832839:ACGA:A	acceptor_gain	0.5600
1:149833093:GCAAC:G	donor_gain	0.5600
1:149833102:ACGAT:A	donor_gain	0.5600
1:149832698:G:GT	donor_gain	0.5500
1:149832703:G:GT	donor_gain	0.5300
1:149832944:T:TA	donor_gain	0.5300
1:149832948:G:GG	donor_gain	0.5300
1:149833110:GGAAG:G	donor_loss	0.5300
1:149833111:GAAG:G	donor_loss	0.5300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 5 via entrez): RS1559763892 (1:149833237 C>CT), RS1571442077 (1:149831804 G>A), RS1571442084 (1:149832423 G>C), RS1571442091 (1:149833016 A>G), RS9436039 (1:149833520 G>A)

Disease associations

OMIM: gene MIM:142750 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5876 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 312 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3919831	AMREDOBRESIB	2	312

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

78 measured of 78 human assays (78 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[1-[(5-fluoro-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	1 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[8-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-5-methyl-4-phenylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-3-methyl-N-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1,5-dimethyl-4-phenoxypyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(3,4-difluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[9-benzyl-2-(4-methylpiperazin-1-yl)purin-8-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)benzimidazol-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3R)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3S)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[5-(oxan-4-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	11 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-4-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methoxyacetamide	IC50	12.8 nM	US-9125915: Antitumor agent
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N-ethyl-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[1-[(6-methyl-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methylacetamide	IC50	17.3 nM	US-9125915: Antitumor agent
6-(4-benzyl-1,5-dimethylpyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(3-benzylimidazo[4,5-b]pyridin-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[6-propan-2-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
methyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	IC50	18.2 nM	US-9125915: Antitumor agent
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2-hydroxyethyl)acetamide	IC50	21 nM	US-9125915: Antitumor agent
6-(1-benzylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	22 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	26 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	28 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	31 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors

ChEMBL bioactivities

65 potent at pChembl≥5 of 66 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3930178
8.52	IC50	3	nM	CHEMBL3938152
8.52	IC50	3	nM	CHEMBL3953268
8.52	IC50	3	nM	CHEMBL3916639
8.40	IC50	4	nM	CHEMBL3979803
8.40	IC50	4	nM	CHEMBL3959499
8.30	IC50	5	nM	CHEMBL3913643
8.30	IC50	5	nM	CHEMBL3939182
8.30	IC50	5	nM	CHEMBL3935504
8.15	IC50	7	nM	CHEMBL3983932
8.15	IC50	7	nM	CHEMBL3920322
8.15	IC50	7	nM	CHEMBL3923899
8.10	IC50	8	nM	CHEMBL3929450
8.10	IC50	8	nM	CHEMBL3923105
8.10	IC50	8	nM	CHEMBL3929086
8.10	IC50	8	nM	CHEMBL3927028
8.05	IC50	9	nM	CHEMBL3941148
8.05	IC50	9	nM	CHEMBL3970690
8.05	IC50	9	nM	CHEMBL3908717
8.05	IC50	9	nM	CHEMBL3951550
8.05	IC50	9	nM	AMREDOBRESIB
8.05	IC50	9	nM	CHEMBL4112988
8.05	IC50	9	nM	CHEMBL3893231
8.01	Kd	9.891	nM	CHEMBL5653589
8.01	ED50	9.891	nM	CHEMBL5653589
8.00	IC50	10	nM	CHEMBL3914807
8.00	IC50	10	nM	CHEMBL3902208
7.96	IC50	11	nM	CHEMBL3907651
7.92	IC50	12	nM	CHEMBL3973914
7.92	IC50	12	nM	CHEMBL3966649
7.89	IC50	13	nM	CHEMBL3928047
7.89	IC50	13	nM	CHEMBL3951605
7.89	IC50	13	nM	CHEMBL4114198
7.85	IC50	14	nM	CHEMBL3919702
7.85	IC50	14	nM	CHEMBL3946335
7.82	IC50	15	nM	CHEMBL3916156
7.82	IC50	15	nM	CHEMBL3937464
7.77	IC50	17	nM	CHEMBL3956797
7.77	IC50	17	nM	CHEMBL3914869
7.75	IC50	18	nM	CHEMBL3891629
7.75	IC50	18	nM	CHEMBL3947502
7.75	IC50	18	nM	CHEMBL3956941
7.70	IC50	20	nM	CHEMBL4115491
7.70	IC50	20	nM	CHEMBL3960315
7.66	IC50	22	nM	CHEMBL3946480
7.58	IC50	26	nM	CHEMBL3929241
7.55	IC50	28	nM	CHEMBL3909523
7.51	IC50	31	nM	CHEMBL3985926
7.51	IC50	31	nM	CHEMBL4107079
7.50	IC50	32	nM	CHEMBL3916033

PubChem BioAssay actives

2 with measured affinity, of 108 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	0.0099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	4.0927	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	3
Smoke	decreases expression, decreases reaction	2
Tunicamycin	increases expression	2
OTX015	affects expression	1
sotorasib	affects cotreatment, increases expression	1
potassium perchlorate	decreases expression	1
sodium arsenite	decreases acetylation	1
hydroquinone	decreases expression	1
monomethylarsonous acid	decreases acetylation	1
licochalcone B	increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Decitabine	decreases expression, decreases reaction	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Berberine	decreases expression	1
Doxorubicin	increases expression	1
Endosulfan	decreases expression	1
Fluorouracil	affects expression	1
Lucanthone	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	increases expression	1
Thapsigargin	increases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	increases expression	1
Acrylamide	increases expression	1
S-Nitrosoglutathione	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175621	Binding	Binding affinity to fluorescein-labeled Histone H4(1-20) by spectrofluorometry	Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2R4	SEES3-1V human HIST2H4A, clone1	Embryonic stem cell	Male
CVCL_A2R5	SEES3-1V human HIST2H4A, clone2	Embryonic stem cell	Male
CVCL_A2R6	SEES3-1V human HIST2H4A, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.